DESCRIPTION (from the application): AD is a degenerative disorder associated with senile plaques and marked reactive microgliosis. Dementia is thought to arise from loss of neurons and decreased synaptic connections. A number of studies have implicated neurotoxins released by microglia activated by Abeta1- 42 as one cause of neuronal and synaptic damage in AD brain. Moreover, it is now widely believed that anti-inflammatory drugs might reduce immune-mediated neuron injury occurring in AD. Based upon extensive pre-clinical testing from in vitro and in vivo models, we have selected 3 candidate drugs as immuno- suppressants for AD. Here, we will examine the ability of immuno-suppressing drugs to reduce production of microglia-derived neurotoxins detected within cerebrospinal fluid and to inhibit microglia responses to Abeta1-42. In Aim 1, we monitor CSF levels for microglia-derived neurotoxic activity found in subjects with MCI and AD. The CSF levels of neurotoxic activity will be compared with cognitive scores and monitored longitudinally in subpopulations. In Aim 2, candidate anti-inflammatory agents will be examined for the ability to suppress Abeta-induced immune responses in AD subjects. If successful, this proposed research will spur the development of new strategies to treat AD dementia.